The long-term objective of the research proposed here is to set the stage for the discovery of a new class of orally bioavailable, small-molecule drugs that target the HIV-1 gp41 pocket. Because the residues that form the gp41 pocket are extremely highly conserved, such drugs are predicted to have broad-spectrum activity and be relatively resistant to the development of ?escape? mutations. This new class of drugs could be particularly useful in patients with viruses that have developed resistance to one or more classes of anti-HIV drugs. Earlier, cyclic D-peptides inhibitors of HIV-1 were isolated that bind to the gp41 pocket. However, in spite of numerous efforts in academia and industry over the past ~15 years, there are no small-molecule HIV-1 inhibitors targeting the gp41 pocket in clinical development. Indeed, the gp41 pocket has been referred to as an ?undruggable? target. Analysis of the structures of the gp41 pocket bound to different protein and peptide ligands indicate that the gp41 pocket is highly malleable. We hypothesize that it is more difficult to identify good small-molecule drug leads for a target that is malleable, as compared to a target that is rigid. We also hypothesize that establishing useful structure-activity relationships (SARs) for chemical analogs of drug leads will be more difficult with a malleable target, as compared to a rigid target. We propose several approaches to ?rigidify? the gp41 pocket. After we have created a rigidified gp41 pocket(s), we will test predictions based on the two hypotheses above. First, we predict that a high-throughput screen (HTPS) with a rigid gp41 pocket will yield better hit rates than the malleable pocket. Second, we predict that we will be able to more readily establish useful SARs with a rigid gp41 pocket than with a malleable one. Ligands identified in this manner are expected to have weaker affinity for the natural (i.e., malleable) gp41 pocket, as compared to the rigidified pocket. In essence, the binding affinity will be decreased by the energy necessary to lock the natural gp41 pocket into a fixed conformation. The key point, however, is that by increasing the success of HTPS efforts and obtaining useful SARs (with the rigid gp41 pocket), it will be possible to optimize binding affinity of the small-molecule hits by medicinal chemistry, so that the energetic cost of locking the natural gp41 pocket into a fixed conformation can be readily paid.